The Integrated Translational Science Center (ITSC) formed between SWOG, Cold Spring Harbor Laboratory (CSHL), and The Jackson Laboratory (JAX) provides a powerful combination of clinical and basic research expertise for application to cancer medicine. CSHL and JAX are both NCI-designated Cancer Centers and represent a significant collective experience in cancer gene discovery, the functional genomics of cancer, innovative tumor modeling, and the development of novel technologies to interrogate the disease. SWOG is a premier clinical trials organization that has established the standard of care for multiple cancer types over the past several decades. This alliance will bridge the gap between the laboratory and the clinic by elucidating the key clinical problems and challenges in oncology that can be addressed in the laboratory, discovering new diagnostic and therapeutic approaches that can be integrated into clinical trials, and providing a conduit for clinical trial results to be re-interpreted in the laboratory. This relationship will lead to a clearer understanding of the mechanisms underlying cancer and advance translational research aimed at developing effective targeted therapies. Both CSHL and JAX have used their extensive knowledge of the molecular alterations in human cancer to generate a diverse array of genetically modified or primary human- derived (PDX) xenograft mouse models of human cancer, and these models will be collectively utilized to identify new therapeutic vulnerabilities, determine mechanisms of primary or secondary drug resistance, and develop novel diagnostic strategies. Such information will be used to generate new hypotheses in regard to potential predictive biomarkers that can be studied in randomized clinical trials being conducted by SWOG. Specific examples of novel expertise include single cell sequencing, circulating DNA analysis, co-clinical trials in animal models, computational prediction of resistance from genomic data, and in silico and animal modeling of therapeutic combinations to optimize initial potency and avoid resistance. The scientific endeavors of CSHL and JAX will therefore inform ongoing clinical trials and establish a mechanism for fostering translational cancer research.